Net clinical benefit of DOACs vs. usual anticoagulation treatment in venous thromboembolism and active cancer: systematic review and meta-analysis.

Patients with active cancer are at high risk of recurrent venous thromboembolism (VTE). Usual treatment includes low molecular weight heparin (LMWH), while vitamin K antagonists (VKAs) have also been used as substitutes for LMWH. Direct oral anticoagulants (DOACs) are considered a beneficial alternative to the usual treatment but are accompanied by an increased rate of bleeding compared to LMWH. We conducted a meta-analysis to evaluate the benefits and harms under a common denomination, namely the net clinical benefit (NCB), between DOACs and usual anticoagulation. The primary outcome was NCB-1, defined as non-fatal VTE, major non-fatal bleedings, and all-cause mortality). Co-primary outcomes were 1) NCB-2 (i.e., NCB-1 and clinically relevant non-major bleedings) and 2) NCB-3 (i.e., fatal or non-fatal VTE and major bleedings). A random-effects model was used to calculate outcome risk ratios and 95% confidence intervals (CI). Prospective Register of Systematic Reviews identification number CRD42021284238. We selected 8 studies (n = 4,4461 patients; mean follow-up, 6 months). The NCB-1 and -2 were not different between DOACs and usual anticoagulation, while the NCB-3 showed a reduction of 28% (95% CI, 10-42%), favoring DOACs. Recurrent VTE was reduced by 40% (95% CI, 25-53%) with DOACs than the usual treatment. Different bleeding outcomes and all-cause mortality were not different between treatments. All primary outcomes did not differ between DOACs and LMWH, while NCB-2 and NCB-3 were reduced with DOACs than VKAs. The NCB of DOACs was similar or more favorable to usual anticoagulation in patients with active cancer due to a substantial reduction of VTE and no bleeding excess.

Global longitudinal strain predicts responders after cardiac resynchronization therapy-a systematic review and meta-analysis.

To evaluate the association between baseline global longitudinal strain (GLS) and ΔGLS (difference of baseline GLS and follow-up) and cardiac resynchronization therapy (CRT) response defined either with clinical or with echocardiographic characteristics. This meta-analysis was performed in accordance to both the Meta-Analysis of Observational Studies in Epidemiology and Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Two independent investigators performed a comprehensive systematic search in MedLine, EMBASE and Cochrane databases through September 2019 without limitations. Data analysis was performed by using the Review Manager software (RevMan), version 5.3, and Stata 13 software. A p value of less than 0.05 (two-tailed) was considered statistically significant. Twelve studies (1004 patients, mean age 63.8 years old, males 69.4%) provided data on the association of baseline GLS with the response to CRT therapy. We found that CRT responders had significantly better resting GLS values compared with non-responders [GLS mean difference -2.13 (-3.03, -1.23), p < 0.001, I2 78%]. Furthermore, CRT responders had significantly greater improvement of GLS at follow-up compared with non-responders [ΔGLS mean difference -3.20 (-4.95, -1.45), p < 0.001, I2 66%]. These associations remained significant in a subgroup analysis including only studies with similar CRT response definition. In this meta-analysis, we found that CRT responders had a baseline and ΔGLS significantly higher than the non-responders strengthening the central role of GLS as a tool for selecting candidates for CRT. Furthermore, improved GLS values after CRT may be used to better define CRT responders.

Overview of salt restriction in the Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean diet for blood pressure reduction.

Despite considerable advances in pharmacological treatments, hypertension remains a major cause of premature morbidity and mortality worldwide since elevated blood pressure (BP) adversely influences cardiovascular and renal outcomes. Accordingly, the current hypertension guidelines recommend the adoption of dietary modifications in all subjects with suboptimal BP levels. These modifications include salt intake reduction and a healthy diet, such as the Dietary Approaches to Stop Hypertension (DASH) diet or the Mediterranean diet (MedDiet), independently of the underlying antihypertensive drug treatment. However, dietary modifications for BP reduction in adults with prehypertension or hypertension are usually examined as stand-alone interventions and, to a lesser extent, in combination with other dietary changes. The purpose of the present review was to summarize the evidence regarding the BP effect of salt restriction in the context of the DASH diet and the MedDiet. We also summarize the literature regarding the effects of these dietary modifications when they are applied as the only intervention for BP reduction in adults with and without hypertension and the potent physiological mechanisms underlying their beneficial effects on BP levels. Available data of randomized controlled trials (RCTs) provided evidence about the significant BP-lowering effect of each one of these dietary strategies, especially among subjects with hypertension since they modulate various physiological mechanisms controlling BP. Salt reduction by 2.3 g per day in the DASH diet produces less than half of the effect on systolic blood pressure (SBP)/diastolic blood pressure (DBP) (-3.0/-1.6 mmHg) as it does without the DASH diet (-6.7/-3.5 mmHg). Although their combined effect is not fully additive, low sodium intake and the DASH diet produce higher SBP/DBP reduction (-8.9/-4.5 mmHg) than each of these dietary regimens alone. It is yet unsettled whether this finding is also true for salt reduction in the MedDiet.

Net clinical benefit of a reduced dose of DOACs in non-valvular atrial fibrillation: A meta-analysis of randomized trials.

BACKGROUND: In standard dosing, direct Oral Anticoagulants (DOACs) are used as an alternative to warfarin to prevent ischemic stroke and systemic embolism in non-valvular Atrial Fibrillation (AF). However, randomized comprehensive evidence considering the efficacy and safety of the low-dose DOACs in the same setting is still lacking. Toward this end, we conducted a meta-analysis of randomized trials to estimate the risk/benefit ratio, in terms of net clinical benefit, by comparing a reduced dose of DOACs and warfarin. METHODS: We searched three electronic databases, covering the period until end-February 2021. All-cause death, non-fatal stroke/systemic embolism, and major bleeding events, with or without the inclusion of myocardial infarction, were used to define two different net clinical benefit outcomes. In addition, we evaluated different component outcomes of net clinical benefit as secondary outcomes. Finally, risk ratios and 95% Confidence Intervals (CI) of each outcome were calculated (random-effects model). RESULTS: In the four randomized trials included (n = 29,779 patients), the net clinical benefit - with or without the inclusion of myocardial infarction - of low-dose DOACs, compared to warfarin, was a 12% (95% CI, 7%-16%) or a 10% (95% CI, 5%-13%) reduction of events, respectively. Compared to warfarin, the reduced dose of DOACs decreased death outcomes, major bleeding events, and hemorrhagic stroke, whereas all thrombotic outcomes were not different among the groups. CONCLUSIONS: DOACs at low dosing present a more favorable net clinical benefit profile compared to warfarin.

Blood pressure control measures and cardiovascular outcomes: a prospective hypertensive cohort.

PURPOSE: We investigated whether blood pressure (BP) control measures, visit-to-visit BP variability, and time in therapeutic range (TTR) are associated with future cardiovascular outcomes in hypertensive patients. MATERIALS AND METHODS: Among 1,408 hypertensive patients without cardiovascular disease, we prospectively evaluated the incident major cardiovascular events over 6 years. In newly diagnosed patients, antihypertensive drug treatment was initiated. We estimated two markers of on-treatment BP control, (1) visit-to-visit BPV as the coefficient of variation of office systolic BP (BP-CV), and (2) TTR calculated as the percentage of office systolic BP measurements within 120-140mmHg across visits. RESULTS: The hypertensive cohort (672 males, mean age 60 years, 31% newly diagnosed) had a mean systolic/diastolic BP of 142/87 mmHg. The mean number of visits was 4.9 ± 2.6, while the mean attained systolic/diastolic BP during follow-up was 137/79 mmHg using 2.7 ± 1.1 antihypertensive drugs. The BP-CV and TTR were 9.1 ± 4.1% and 45 ± 29%, respectively, and the incidence of the composite outcome was 8.3% (n = 117). After adjustment for relevant confounders and standardization to z-scores, BP-CV and TTR were associated with a 43% (95% CI, 27-62%) increase and a 33% (95% CI, 15-47%) reduction in the outcome. However, the joint evaluation of TTR and BP-CV in a common multivariable model indicated that a standardized change of TTR was associated with the outcome to a greater extent than BP-CV (mean hazard ratios of 30% vs. 24%, respectively). When combined with the higher BP standardized-CV quartile, the lower TTR quartile predicted the outcome by 2.3 times (95% CI, 1.1-5.4) compared to the inverse TTR and BP-CV quartile pattern. CONCLUSION: High BP-CV or low TTR was associated with future cardiovascular events in a cohort of treated hypertensive patients. As a determinant, the extent of TTR value appears greater than BP-CV when these measures are considered in the same multivariable model.

Antidiabetic drugs and blood pressure changes.

New era antidiabetic drugs are characterized by cardiovascular safety, including specific outcome benefits observed in randomized clinical trials (RCTs). It has been postulated that the favorable effects of new antidiabetic agents are related both to better control of blood pressure (BP) levels and to activation of multiple anti-atherosclerotic properties. In this review, we aimed to assess whether antidiabetic drugs have a pressor effect in glucose control and outcome-oriented RCTs, and to summarize the activated pathophysiological mechanisms relevant to BP control following the use of different antidiabetic drug classes. We also tried to determine which, if any, are the BP-lowering effects of more intense vs less intense glucose-lowering strategy irrespectively of trial antidiabetic regimen. To provide more robust results and evidence-based argumentation, a meta-analysis of placebo-controlled antidiabetic drug RCTs was undertaken to estimate the ongoing BP reduction for all considered and each separate drug class alone. This quantitative synthesis might be helpful for the clinician 1) to select or avoid the use of some classes of antidiabetic agents with a potential favorable or adverse pressor effect, respectively 2) to organize the overall drug regimen in patients with diabetes mellitus and minimize side effects because of concomitant use of drugs with established pressor effect (i.e. antihypertensive agents). This review was also organized to indicate whether BP change associated with different antidiabetic treatments may explain the specific macrovascular outcome benefits. Between all antidiabetic drugs including exogenous insulin, only sodium-glucose cotransporter 2 inhibitors produce a clinically important BP-lowering effect, but this BP reduction alone cannot explain the observed cardiovascular benefit.

Is there a blood pressure lowering effect of MRAs in heart failure? An overview and meta-analysis.

Although mineralocorticoid antagonists (MRAs) have been proposed as effective fourth-line blood pressure (BP) lowering agents in resistant hypertension, this effect in heart failure is undetermined. In this synthesis of heart failure randomized controlled trials (RCTs), we evaluated the extent of BP lowering following MRA treatment against placebo. We searched Medline and the Cochrane Collaboration Library databases from 1991 to September 2016 for RCTs, in which MRAs were compared with placebo. The quality of RCTs was assessed with Cochrane risk of bias tool. Outcomes were the extent of systolic and diastolic BP lowering. We included seven studies (13,354 patients, 65.8% males, mean age of 66.3 years, mean follow-up period of 9.4 months, mean baseline BP of 123.5/75.0 mmHg) of MRAs compared with placebo. MRAs were not significantly associated with systolic - 1.8 (95% CI: - 8.0, 4.4) mmHg or diastolic - 0.3 (95% CI: - 3.4, 2.7) mmHg, BP reduction. Although systolic BP was not lowered by spironolactone, diastolic BP was lowered by - 3.0 (95% CI: - 3.4, - 2.6) mmHg. Eplerenone treatment did not significantly lowered systolic [- 0.04 (95% CI: - 4.4, 4.3) mmHg], but it was associated with minimal diastolic BP increase [1.0 (95% CI: 0.5, 1.53) mmHg]. MRAs were not associated with systolic and diastolic BP reduction in heart failure patients. This finding suggests that MRAs should be used according to their indications in heart failure independently of initial BP levels.

Uric acid as an independent predictor of coronary artery disease in essential hypertension: Data from an 8-year-follow-up study.

The role of serum uric acid (SUA) in cardiovascular risk prediction remains to be further determined. We assessed the predictive value of SUA for the incidence of coronary artery disease (CAD) in 2287 essential hypertensive patients who were followed up for a mean period of 8 years. The distribution of SUA levels at baseline was split by the median (5.2 mg/dL) and subjects were classified into those with high and low values. Hypertensives who developed CAD (n = 57) compared to those without CAD at follow-up (n = 2230) had at baseline higher SUA. In multivariate Cox regression model, among established confounders, high SUA (hazard ratio = 1.216, P = .016) turned out to be independent predictor of CAD. In essential hypertensive patients SUA independently predicts CAD.

Randomized controlled trials of blood pressure lowering in hypertension: a critical reappraisal.

Sixty-eight blood pressure (BP)-lowering randomized controlled trials (defined as randomized controlled trials comparing active treatment with placebo, or less active treatment, achieving a BP difference, performed between 1966 and end 2013 in cohorts with ≥ 40% hypertensive patients, and exclusive of trials in acute myocardial infarction, heart failure, acute stroke, and dialysis) were identified and meta-analyzed grouping the randomized controlled trials on the basis of clinically relevant questions: (1) does BP lowering reduce all types of cardiovascular outcome? (2) Is prevention of all outcomes proportional to the extent of systolic, diastolic, and pulse BP? (3) Have all classes of BP-lowering drugs been shown capable of reducing all types of cardiovascular outcome? (4) Is BP lowering beneficial when intervention is initiated at any grade (or stage) of hypertension? (5) Do BP-lowering randomized controlled trials provide evidence about systolic BP and diastolic BP targets of treatment? (6) Should BP-lowering treatment be preferentially addressed to patients in higher risk categories promising larger absolute treatment benefits? The results of these meta-analyses provide further support to current hypertension treatment guidelines by showing that BP lowering can significantly reduce major cardiovascular outcomes largely independent of the agents used, significant risk reduction is found at all hypertension grades (stages), and when systolic BP is lowered below a cut off of 140 mm Hg with some further reduction limited to stroke at systolic BP values just <130 mm Hg. Absolute risk reduction progressively increases higher is total cardiovascular risk, but this greater benefit is associated with a progressively higher residual risk, ie, higher treatment failures.

Combination drug treatment in hypertension.

Combination treatment of hypertension has been introduced almost 50 years ago, because of the marked blood pressure (BP) elevation of recruited patients in the early randomized controlled trials of BP lowering. However, in all subsequent trials combination treatment was per protocol anticipated irrespectively of the initial randomized treatment to ensure either a desirable BP lowering or a comparable level of BP reduction among arms. Beyond clinical trials, combination treatment is mainly used in the clinical practice to reinforce ongoing single-agent treatment to achieve hypertension control. Renin-angiotensin system inhibiting drugs are the cornerstone of combination treatment of hypertension because they have been repeatedly tested in clinical trials in combination with other agents either from the beginning or during the follow-up. Effective BP lowering following combination treatment depends on the activation of complementary pathophysiological pathways but different agents can stimulate a common mode of action more effectively. The rate of adverse events following combination treatment may be reduced because effects of each agents are reciprocally counterbalanced. Nevertheless, aggressive BP lowering independently of the implemented combination is associated with increase of treatment discontinuations. In the management of resistant hypertension, a fourth-line agent used on top of the failing triple (diuretic-based) combination is effective to control hypertension only in 50% of patients. At present, it is questioned whether combination treatment of hypertension should be used alternatively to monotherapy in newly-diagnosed hypertensive patients without marked BP elevation or at low cardiovascular risk. Selection between free and fixed-dose combination treatment should be individualized depending on clinical criteria.

Anti-ischemic and pleiotropic effects of ranolazine in chronic coronary syndromes.

The vast majority of antianginal drugs decrease heart rate and or blood pressure levels or the inotropic status of the left ventricle to decrease myocardial oxygen consumption (MVO2) and thus anginal symptoms. Ranolazine presents a completely different mechanism of action, which reduces the sodium-dependent calcium overload inhibiting the late sodium current. Current European Society of Cardiology (ESC) guidelines for the management of angina in patients with chronic coronary symptoms recommend the use of several drugs such as ranolazine, b-blockers, calcium channel blockers, long-acting nitrates, ivabradine, nicorandil and trimetazidine for angina relief. However, ranolazine, in addition to symptom relief properties, is an antianginal drug showing favorable effects in decreasing the arrhythmic burden and in ameliorating the glycemic profile of these patients. In this review, we summarize the available data regarding the antianginal and pleiotropic effects of this drug.

Revisiting Cardiovascular Benefits of Blood Pressure Reduction in Primary and Secondary Prevention: Focus on Targets and Residual Risk-A Systematic Review and Meta-Analysis.

BACKGROUND: Previous meta-analyses resurrected the debated statement "the lower, the better" following blood pressure (BP)-lowering treatment. We investigated the benefits of BP-lowering treatment at different BP targets by prevention category. METHODS: The meta-analysis protocol was registered at the International Prospective Register of Systematic Reviews (CRD42022379249). The database included 115 BP-lowering or comparison trials from patients with (n=241 089) or without (n=198 937) previous cardiovascular events. Prevention disease groups were stratified by in-treatment achieved BP, drug class versus placebo, and drug class versus other classes. Risk ratios and 95% CIs of major adverse cardiovascular events were calculated. RESULTS: Following a standard (10/5 mm Hg) BP reduction, major adverse cardiovascular event relative risk reductions were not different between prevention groups (primary, 25% [95% CI, 18%-31%]; secondary, 28% [95% CI, 20%-37%]). For achieved systolic BP of at least 140 mm Hg, between 130 and 140 mm Hg, and <130 mm Hg (nadir, 125 mm Hg), (1) risk ratios of major adverse cardiovascular events and absolute risk reductions were not different between prevention groups across systolic BP strata, and (2) residual risk, though 4.1× greater in secondary than primary prevention, decreased in primary prevention from higher to lower systolic BP targets. The effect of separate drugs versus others on the primary outcome was not different between prevention groups. CONCLUSIONS: BP-lowering treatment benefits did not differ by prevention group to a nadir of 125 mm Hg for systolic BP. Although residual risk in secondary prevention is higher than in primary prevention, it gradually decreases at progressively lower systolic BP targets in primary prevention. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42022379249.

Rationale for the Inclusion of ß-Blockers Among Major Antihypertensive Drugs in the 2023 European Society of Hypertension Guidelines.

We address the reasons why, unlike other guidelines, in the 2023 guidelines of the European Society of Hypertension ß-blockers (BBs) have been regarded as major drugs for the treatment of hypertension, at the same level as diuretics, calcium channel blockers, and blockers of the renin-angiotensin system. We argue that BBs, (1) reduce blood pressure (the main factor responsible for treatment-related protection) not less than other drugs, (2) reduce pooled cardiovascular outcomes and mortality in placebo-controlled trials, in which there has also been a sizeable reduction of all major cause-specific cardiovascular outcomes, (3) have been associated with a lower global cardiovascular protection in 2 but not in several other comparison trials, in which the protective effect of BBs versus the other major drugs has been similar or even greater, with a slightly smaller or no difference of global benefit in large trial meta-analyses and a similar protective effect when comparisons extend to BBs in combination versus other drug combinations. We mention the large number of cardiac and other comorbidities for which BBs are elective drugs, and we express criticism against the exclusion of BBs because of their lower protective effect against stroke in comparison trials, because, for still uncertain reasons, differences in protection against cause-specific events (stroke, heart failure, and coronary disease) have been reported for other major drugs. These partial data cannot replace global benefits as the main deciding factor for drug choice, also because in the general hypertensive population whether and which type of event might occur is unknown.

Atrial fibrillation in the setting of cardiac amyloidosis - A review of the literature.

Cardiac amyloidosis (CA) is related to the aggregation of insoluble fibrous deposits of misfolded proteins within the myocardium. Transthyretin amyloidosis (ATTR) and immunoglobulin light-chain amyloidosis are the main forms of CA. Atrial fibrillation (AF) is a common arrhythmia in CA patients, especially in those with ATTR amyloidosis. Increased atrial preload and afterload, atrial enlargement, enhanced atrial wall stress, and autonomic dysfunction are the main mechanisms of AF in CA patients. CA is associated with the formation of endocardial thrombi and systemic embolism. The promoters of thrombogenesis include endomyocardial damage, blood stasis, and hypercoagulability. The prevalence of thrombi in patients with AF remains elevated despite long-term anticoagulation. Consequently, transesophageal ultrasound examinations before cardioversion should be performed to exclude endocardiac thrombi despite anticoagulation. Furthermore, the CHA2DS2-VASc score should not be used to assess the thromboembolic risk in CA patients with AF. Rate control is challenging in patients with CA, while rhythm control is the preferred treatment option, especially in the early stages of the disease process. Although catheter ablation is an effective treatment option, more data are needed to explore the role of the procedure in CA patients.

One-year outcomes following a hypertensive urgency or emergency.

There are scarce data on the comparative prognosis between patients with hypertensive emergencies (HE), urgencies (HU), and those without HU or HE (HP). Our study aimed to compare cardiovascular (CV) outcomes of HE, HU, and HP during a 12-month follow-up period. The population consisted of 353 consecutive patients presenting with HE or HU in a third-care emergency department and subsequently referred to our hypertension center for follow-up. After both groups completed scheduled follow-up visits, patients with HU were matched one-to-one by age, sex, and hypertension history with HP who attended our hypertension center during the same period. Primary outcomes were 1) a recurrent hypertensive HU or HE event and 2) non-fatal CV events (coronary heart disease, stroke, heart failure, or CV interventions), while secondary outcomes were 1) all-cause death, 2) CV death, 3) non-CV death, and 4) any-cause hospitalization. Events were prospectively registered for all three groups. During the study period, 81 patients were excluded for not completing follow-up. Among eligible patients(HE = 94; HU = 178), a total of 90 hospitalizations and 14 deaths were recorded; HE registered greater CV morbidity when compared with HU (29 vs. 9, HR 3.43, 95 % CI 1.7-6.9, p = 0.001), and increased CV mortality (8 vs. 1, HR 13.2, 95 % CI 1.57-110.8, p = 0.017). When opposing HU to HP, events did not differ substantially. Cox regression models were adjusted for age, sex, CV and chronic kidney disease, diabetes mellitus, and smoking. During 1-year follow-up, the prognosis of HU was better than HE but not different compared to HP. These results highlight the need for improved care of HU and HE.

Management of hypertensive disorders in pregnancy: a Position Statement of the European Society of Hypertension Working Group 'Hypertension in Women'.

Hypertensive disorders in pregnancy (HDP), remain the leading cause of adverse maternal, fetal, and neonatal outcomes. Epidemiological factors, comorbidities, assisted reproduction techniques, placental disorders, and genetic predisposition determine the burden of the disease. The pathophysiological substrate and the clinical presentation of HDP are multifarious. The latter and the lack of well designed clinical trials in the field explain the absence of consensus on disease management among relevant international societies. Thus, the usual clinical management of HDP is largely empirical. The current position statement of the Working Group 'Hypertension in Women' of the European Society of Hypertension (ESH) aims to employ the current evidence for the management of HDP, discuss the recommendations made in the 2023 ESH guidelines for the management of hypertension, and shed light on controversial issues in the field to stimulate future research.

Effect of DASH vs. mediterranean diet accompanied by a salt restriction on metabolic syndrome and cardiometabolic risk factors in adults with high normal blood pressure or grade 1 hypertension: secondary analyses of a randomized controlled trial.

OBJECTIVE: Lifestyle interventions are recommended as the first-line treatment to control metabolic syndrome components and improve cardiometabolic risk factors. However, studies directly comparing the cardiometabolic effects of the Dietary Approaches to Stop Hypertension (DASH) vs. the Mediterranean diet (MedDiet) accompanied by salt restriction are currently lacking. Thus, with the present secondary analyses of a randomized trial, we aimed to assess the cardiometabolic effects of a 3-month intensive dietary intervention implementing salt restriction alone or on top of the DASH and MedDiet compared to no/minimal intervention in never drug-treated adults with high normal blood pressure (BP) or grade 1 hypertension. METHODS: We randomly assigned individuals to the control group (CG, n = 60), salt restriction group (SRG, n = 60), DASH diet with salt restriction group (DDG, n = 60), or MedDiet with salt restriction group (MDG, n = 60). RESULTS: According to the intention-to-treat analysis, the DDG and the MDG had lower odds ratio (OR) (95% CI) of metabolic syndrome [0.29 (0.12, 0.72), and 0.15 (0.06, 0.41), respectively] compared to the CG. Moreover, the MDG had lower odds of metabolic syndrome compared to the SRG and lower odds of elevated BP levels than the DDG and the SRG. Moreover, total and LDL-cholesterol, fasting glucose, HbA1c, and systolic/diastolic BP were reduced in all three intervention groups compared to the CG. CONCLUSION: On a background of salt restriction, the MedDiet was superior in BP reduction, but the DASH and MedDiet reduced the prevalence of metabolic syndrome to the same extent.